OBJECTIVE:The efficacy and safety of subcutaneous tocilizumab (TCZ-SC) versus subcutaneous placebo (PBO-SC) was evaluated in patients with rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs in the BREVACTA study. METHODS:Patients (n = 656) were randomized 2:1 to receive TCZ-SC 162 mg every other week or PBO-SC every other week for 24 weeks; 20% previously received anti-tumor necrosis factor treatment. Escape therapy with TCZ-SC 162 mg weekly was offered from week 12 for inadequate response. The primary end point was the American College of Rheumatology 20% improvement (ACR20) response at week 24. The key secondary outcomes were radiographic progression and safety. RESULTS:TCZ-SC was superior to PBO-SC for ACR20 response at week 24 (60.9% versus 31.5%; P < 0.0001). All secondary end points showed TCZ-SC to be superior to PBO-SC, including ACR50 and ACR70 response (40% and 20% for TCZ-SC, respectively, and 12% and 5% for PBO-SC, respectively; P < 0.0001 for both) and Disease Activity Score in 28 joints (DAS28) remission (DAS28 <2.6; 32% versus 4% [P < 0.0001]). The mean change in modified Sharp/van der Heijde score was significantly lower in the TCZ-SC group than the PBO-SC group (0.62 versus 1.23; P = 0.0149). Adverse events (AEs) and serious AEs (SAEs) were comparable between the TCZ-SC and PBO-SC groups; 4.6% and 3.7% of patients had at least 1 SAE, respectively, and infection was the most common SAE in 2.1% and 1.8% of patients, respectively. More injection site reactions occurred with TCZ-SC than PBO-SC (7.1% versus 4.1%). No anaphylaxis or serious hypersensitivity reactions occurred. There were 3 deaths in the TCZ-SC group and 0 in the PBO-SC group. CONCLUSION:TCZ-SC every other week had significantly greater efficacy, including ACR end points and inhibition of joint damage, compared with PBO-SC. TCZ-SC was well tolerated and its safety profile was comparable with that of previous intravenous TCZ studies.

BACKGROUNDSystemic juvenile idiopathic arthritis (JIA) is the most severe subtype of JIA; treatment options are limited. Interleukin-6 plays a pathogenic role in systemic JIA.METHODSWe randomly assigned 112 children, 2 to 17 years of age, with active systemic JIA (duration of ≥6 months and inadequate responses to nonsteroidal antiinflammatory drugs and glucocorticoids) to the anti-interleukin-6 receptor antibody tocilizumab (at a dose of 8 mg per kilogram of body weight if the weight was ≥30 kg or 12 mg per kilogram if the weight was <30 kg) or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients meeting the predefined criteria for nonresponse were offered open-label tocilizumab. All patients could enter an open-label extension.RESULTSAt week 12, the primary end point (an absence of fever and an improvement of 30% or more on at least three of the six variables in the American College of Rheumatology [ACR] core set for JIA, with no more than one variable worsening by more than 30%) was met in significantly more patients in the tocilizumab group than in the placebo group (64 of 75 [85%] vs. 9 of 37 [24%], P<0.001). At week 52, 80% of the patients who received tocilizumab had at least 70% improvement with no fever, including 59% who had 90% improvement; in addition, 48% of the patients had no joints with active arthritis, and 52% had discontinued oral glucocorticoids. In the double-blind phase, 159 adverse events, including 60 infections (2 serious), occurred in the tocilizumab group, as compared with 38, including 15 infections, in the placebo group. In the double-blind and extension periods combined, 39 serious adverse events (0.25 per patient-year), including 18 serious infections (0.11 per patient-year), occurred in patients who received tocilizumab. Neutropenia developed in 19 patients (17 patients with grade 3 and 2 patients with grade 4), and 21 had aminotransferase levels that were more than 2.5 times the upper limit of the normal range.CONCLUSIONSTocilizumab was efficacious in severe, persistent systemic JIA. Adverse events were common and included infection, neutropenia, and increased aminotransferase levels. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00642460.).

Microvascular changes occur early in diabetes mellitus. Doppler ultrasound enables non-invasive identification of ocular microvascular haemodynamics through interrogation of blood flow velocity waveforms. Wave decomposition permits the spectrum of sinusoidal components comprising flow velocity waveforms to be quantified. We hypothesised that comprehensive interrogation of waveforms would be more sensitive in identifying microvascular abnormalities than traditional analysis employing the resistive index. Thirty-four subjects with type 2 diabetes and 20 healthy controls between 30 and 70 years old were recruited. Doppler flow velocity waveform signals were captured from the ophthalmic and carotid arteries under standardised conditions. The signals were analysed using a wave decomposition algorithm and the sinusoidal components of average waveforms were compared between groups at both arterial sites. The diabetes group displayed significant differences in the lower frequency sinusoidal components of both the ophthalmic artery (p<0.001) and, to a lesser extent, the carotid artery (p<0.05) waveforms compared with controls, with no difference noted in the resistive index at either site. We conclude that wave decomposition analysis of Doppler flow velocity waveforms, recorded in proximity of the terminal vascular bed of interest, can identify subtle microvascular haemodynamic abnormalities not detected by traditional methods of analysis.

Osteoporosis, although considered less common, still occurs in men. We present a cross-sectional study of a group of Northern Ireland men with low-trauma forearm fractures to determine the presence of osteoporosis and screen for secondary causes of low bone mineral density. Male patients aged 30-75 years, presenting with distal forearm fracture in 2000-2001 in Northern Ireland, were identified through a Colles fracture database. A total of 37 subjects consented to have bone mineral density measurements undertaken at the femoral neck, spine and forearm using a Lunar expert bone densitometer. Twenty-seven percent of the men had osteoporosis at the spine, femoral neck or forearm, as defined by a bone mineral density score of less than -2.5. We also found that 49% of patients had vitamin D insufficiency or deficiency, 27% had low serum testosterone, 14% had abnormal liver function test results, and 14% had raised parathyroid hormone. Only one patient received advice or treatment regarding osteoporosis at the time of fracture. Increased awareness of male osteoporosis and the need for screening for potential secondary causes in this group of patients is required, both at primary and secondary care level.

Objective: To compare high- resolution ultrasound ( HRUS) with conventional radiography in the detection of erosions in the first metatarsophalangeal joints ( 1st MTPJs) of patients with gout and to identify the characteristic sonographic features of gout.Methods: HRUS examination of the 1st MTPJs of both feet was performed by two independent sonographers. The presence of joint and soft- tissue pathology was recorded. x Ray examination of the feet was performed on the same day and reported by the same radiologist.Results: 39 male patients with gout and 22 age- matched control subjects ( 14 with an inflammatory arthropathy and 8 disease free) were studied. The agreement on erosion between HRUS and x ray was poor, k = 0.229 ( non- weighted), with McNemar's test being significant ( p < 0.001) indicating a large number of false negative x rays. 22 MTPJs in patients with gout had never been subjected to a clinical attack of acute gout. In these MTPJs, there were 10 erosions detected by HRUS and 3 erosions on x ray. HRUS features significantly more prevalent in the patients with gout were hard and soft tophus- like lesions ( p < 0.01) and the double contour sign ( p < 0.01).Conclusions: These data show that HRUS may assist in the management of gout in two ways: first, by aiding in the diagnosis by identifying the sonographic features that may be representative of the disease, and, second, by allowing the early detection of erosive joint damage and/ or tophaceous deposits even in clinically silent joints.

Structural and functional changes in wall and endothelial components of arterial blood vessels underlie the accelerated vascular disease progression in systemic lupus erythematosus (SLE). Using pulse contour analysis we sought to determine if subclinical vascular abnormalities could be identified in a well-characterised cohort of patients with SLE who had no increase in traditional cardiovascular risk factors. Radial artery pressure waveforms were obtained by applanation tonometry and pressure envelopes were analysed by descriptive and model-based approaches. Waveshape morphology was quantified by a novel eigenvector approach and model-based compliance indices of the large arteries (C1, capacitative arterial compliance) and small arteries (C2, reflective arterial compliance) were derived using a third-order four-element modified Windkessel model. Data were recorded from 30 patients with SLE (mean age 44 7 years and mean SLAM-R 10 +/- 4) and 19 age-matched control subjects. Significant differences in the lower frequency sinusoidal components of the pressure waveforms were evident between groups (P < 0.05). Both C1 and C2 were significantly reduced in patients with SLE: C1 mean +/- SD 13.5 +/- 4.0 ml/mmHg x10 versus C1 17.5 +/- 4.8 ml/mmHg x10 (P = 0.003 in patients vs. controls, respectively) and C2 5.2 +/- 3.4 ml/mmHg x100 versus C2 9.4 +/- 2.8 ml/mmHg x100 (P < 0.001 in patients vs. controls, respectively). In this group of SLE patients, without an excess of traditional cardiovascular risk factors and SLAM-R scores indicating mild disease, descriptive and model-based analysis of arterial waveforms identified vascular abnormalities at a preclinical stage.

Objective—Impaired flow-mediated dilation (FMD) occurs in disease states associated with atherosclerosis, including SLE. The primary hemodynamic determinant of FMD is wall shear stress, which is critically dependent on the forearm microcirculation. We explored the relationship between FMD, diastolic shear stress (DSS), and the forearm microcirculation in 32 patients with SLE and 19 controls. Methods and Results—DSS was calculated using (mean diastolic velocity×8×blood viscosity)/baseline brachial artery diameter. Doppler velocity envelopes from the first 15 seconds of reactive hyperemia were analyzed for resistive index (RI), and interrogated in the frequency domain to assess forearm microvascular hemodynamics. FMD was significantly impaired in SLE patients (median, 2.4%; range, −2.1% to 10.7% versus median 5.8%; range, 1.9% to 14%; P<0.001). DSS (dyne/cm2) was significantly reduced in SLE patients (median, 18.5; range, 3.9 to 34.0 versus median 21.8; range, 14.1 to 58.7; P=0.037). A strong correlation between FMD and DSS, rs=0.65, P=0.01 was found. Postischemic RI was not significantly different between the 2 groups; however, there were significant differences in the power-frequency spectrums of the Doppler velocity envelopes (P<0.05). Conclusions—These data suggest that in SLE, altered structure and function of the forearm microcirculation contributes to impaired FMD through a reduction in shear stress stimulus.

We report a 54 year old female whose successful treatment of cerebral lupus with rituximab was complicated by the development of streptococcus intermedius, on valves damaged by Libman-Sacks endocarditis more than 20 years previously.

Fibromyalgia syndrome is a chronic musculoskeletal disorder characterised by widespread pain, sleep disturbance, headache, stiffness and fatigue. There are a number of potential detrimental factors on bone health in patients with fibromyalgia syndrome including immobility, depression, lack of sunlight and poor nutrition. In this article, the literature relating to fibromyalgia syndrome and bone health is reviewed, and evidence is provided for the potential role of physiotherapy in treating fibromyalgia and maintaining bone health.